In this session, the panel of experts described the recent advances in pharmacotherapy for patients with sleep-disordered breathing. The experts also discussed the impact of weight loss management and the identification of different pathophysiological traits, including upper airway muscle function, respiratory control, arousal from sleep and upper airway anatomy, and the choice of pharmacological drug classes.
This talk discusses the major pharmacological options for weight loss management in patients with sleep-disordered breathing. The mechanisms of action of these pharmacological agents were also highlighted. The prevalence of obesity is rising globally, leading to an increased prevalence of obstructive sleep apnea (OSA) in Western countries and underdeveloped and developing countries. There is an intimate relationship between body weight and apnea-hypopnea index (AHI). Obesity and overweight can be managed using weight-reducing interventions that include diet, physical exercise, pharmacotherapy, and bariatric surgery. Pharmacological approaches for weight reduction in sleep-disordered breathing (SDB) include orlistat in combination with diet. Orlistat acts by inhibiting gastrointestinal lipase. By blocking lipase activity, orlistat inhibits dietary triglycerides from being broken down into absorbable free fatty acids. The side effects of orlistat include diarrhoea, steatorrhea, and ADEK deficiency. A randomized controlled trial demonstrated that orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over two years. Orlistat can be administered in patients with obesity with a body mass index (BMI) of over 30 kg/m2 and patients with a BMI greater than 28 kg/m2 and the presence of risk factors, including hypertension, diabetes, and dyslipidemias.
GLP-1 receptor agonists can also be used for weight reduction in SDB. By activating the GLP-1 receptor, they mimic GLP-1. Thus satiety is increased while hunger and appetite are decreased, leading to less food intake. A study by Blackman A et al. showed that liraglutide 3.0 mg as an adjunct to diet and exercise was generally well tolerated and produced more significant reductions than placebo in AHI, body weight, SBP and HbA1c in patients with obesity and moderate/severe OSA significantly. The results confirmed that weight loss improves OSA-related parameters. The XENSOR study demonstrated greater effectiveness in weight loss with liraglutide compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.
The next talk in the session discussed the role of upper airway muscle function in the pathophysiology of sleep-disordered breathing. The pathogenesis of OSA is multifactorial. The knowledge of the activity of upper airway muscles comes from animal studies. A review suggested that episodic hypoxia is responsible for the progression of OSA through impairment of the neural control systems that regulate upper airway patency and through altered respiratory muscle contractile function, leading to the establishment of a vicious cycle of further airway obstruction and hypoxia insult that can chronically exacerbate the condition. The study concluded that chronic intermittent hypoxia contributes to the pathophysiology of SDB. Recent evidence indicates that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. A study showed that combining atomoxetine and oxybutynin administered orally before bedtime significantly reduced OSA severity. The combination lowered AHI by 63%. Noradrenergic agents, reboxetine, and antimuscarinic hyoscine butylbromide have also reduced sleep apnea severity. However, there is currently insufficient evidence to recommend any pharmacotherapy for OSA.
The talk also focused on the current perspectives in pharmacotherapy targeting brain breathing regulation. Carbonic anhydrase (CA) is an enzyme occurring in multiple isoforms in the body and is widely distributed. CA-inhibitors may have beneficial cardiovascular and metabolic effects in patients with OSA. Sulthiame (STM) has been shown to reduce OSA and improve oxygenation and sleep quality. In addition, STM reduces loop gain and time delay in patients with OSA. Clinical studies of CA-inhibitors in OSA are warranted to identify specific responder groups, optimal dose levels, long-term efficacy and effect on clinical outcomes.
In the session, the influence of pharmacotherapy on arousal threshold was also discussed. One-third of individuals with OSA have a lower arousal threshold as a key pathogenic mechanism. The arousal threshold is the level of the ventilatory drive at which an individual awakens. The arousal threshold can be modified by decreasing overall brain arousability or preventing CO2-mediated arousals. Benzodiazepines do not seem to have a role in increasing the arousal threshold. Non-benzodiazepines and serotoninergic drugs appear safe in OSA and may be beneficial in combination therapy. Currently, combination therapy is the only way through which drugs that increase arousal threshold can be proposed.
European Respiratory Society (ERS) International Congress 2022, 3rd-6th Sept. 2022, Barcelona